Psychopathology in Williams Syndrome: the effect of individual differences across the life span

The present research aimed to comprehensively explore psychopathology in Williams syndrome (WS) across the lifespan and evaluate the relationship between psychopathology and age category (child or adult), gender and cognitive ability. The parents of 50 participants with WS, aged 6-50 years, were interviewed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL). The prevalence of a wide range of Axis I DSM-IV disorders was assessed. In addition to high rates of anxiety and Attention Deficit Hyperactivity Disorder (ADHD) (38% and 20% respectively), 14% of our sample met criteria for a depressive disorder and 42% of participants were not experiencing any significant psychopathological difficulties. There was some evidence for different patterns of psychopathology between children and adults with WS and between males and females. These relationships were largely in keeping with those found in the typically developing population, thus supporting the validity of applying theory and treatment approaches for psychopathology in the typically developing population to WS.

Resting state cortico-thalamic-striatal connectivity predicts pesponse to dorsomedial prefrontal rTMS in major depressive disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for Major Depressive Disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting state functional connectivity predicted response to treatment with rapid transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased sgACC-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Randomized controlled trial of parent-enhanced CBT compared with individual CBT for obsessive-compulsive disorder in young people

Objective: Obsessive-compulsive disorder (OCD) in young people can be effectively treated with Cognitive Behavior Therapy (CBT). Practice guidelines in the United Kingdom recommend that CBT be delivered with parental or family involvement; however, there is no evidence from randomized trials that this enhances effectiveness. The aim of this trial was to assess if CBT with high parental involvement was more effective than CBT with low parental involvement (individual CBT) in reducing symptoms of OCD. Method: Fifty young people ages 12–17 years with OCD were randomly allocated to individual CBT or parent-enhanced CBT. In parent-enhanced CBT parents attended all treatment sessions; in individual CBT, parents attended only Sessions 1, 7, and the final session. Participants received up to 14 sessions of CBT. Data were analyzed using intent-to-treat and per-protocol methods. The primary outcome measure was the Children’s Yale-Brown Obsessive Compulsion Scale (Scahill et al., 1997). Results: Both forms of CBT significantly reduced symptoms of OCD and anxiety. Change in OCD symptoms was maintained at 6 months. Per-protocol analysis suggested that parent-enhanced CBT may be associated with significantly larger reductions in anxiety symptoms. Conclusions: High and low parental involvement in CBT for OCD in young people were both effective, and there was no evidence that 1 method of delivery was superior on the primary outcome measure. However, this study was small. Future trials should be adequately powered and examine interactions with the age of the young person and comorbid anxiety disorders.

Expression of the Rap1 guanine nucleotide exchange factor, MR-GEF, is altered in individuals with bipolar disorder

In the rodent forebrain GABAergic neurons are generated from progenitor cells that express the transcription factors Dlx1 and Dlx2. The Rap-1 guanine nucleotide exchange factor, MR-GEF, is turned on by many of these developing GABAergic neurons. Expression of both Dlx1/2 and MR-GEF is retained in both adult mouse and human forebrain where, in human, decreased Dlx1 expression has been associated with psychosis. Using in situ hybridization studies we show that MR-GEF expression is significantly down-regulated in the forebrain of Dlx1/2 double mutant mice suggesting that MR-GEF and Dlx1/2 form part of a common signalling pathway during GABAergic neuronal development. We therefore compared MR-GEF expression by in situ hybridization in individuals with major psychiatric disorders (schizophrenia, bipolar disorder, major depression) and control individuals. We observed a significant positive correlation between layers II and IV of the dorso-lateral prefrontal cortex (DLPFC) in the percentage of MR-GEF expressing neurons in individuals with bipolar disorder, but not in individuals with schizophrenia, major depressive disorder or in controls. Since MR-GEF encodes a Rap1 GEF able to activate G-protein signalling, we suggest that changes in MR-GEF expression could potentially influence neurotransmission.

Substitutional and orientational disorder in organic crystals: a symmetry-adapted ensemble model

Modelling of disorder in organic crystals is highly desirable since it would allow thermodynamic stabilities and other disorder-sensitive properties to be estimated for such systems. Two disordered organic molecular systems are modeled using a symmetry-adapted ensemble approach, in which the disordered system is treated as an ensemble of the configurations of a supercell with respect to substitution of one disorder component for another. Computation time is kept manageable by performing calculations only on the symmetrically inequivalent configurations. Calculations are presented on a substitutionally disordered system, the dichloro/dibromobenzene solid solution, and on an orientationally disordered system, eniluracil, and the resultant free energies, disorder patterns, and system properties are discussed. The results are found to be in agreement with experiment following manual removal of physically implausible configurations from ensemble averages, highlighting the dangers of a completely automated approach to organic crystal thermodynamics which ignores the barriers to equilibration once the crystal has been formed.

Examining vulnerability to involuntary memories in schizophrenia comorbid with post-traumatic stress disorder

The current study explored whether individuals diagnosed with schizophrenia and a high level of PTSD symptoms experience more frequent neutral intrusive memories than individuals diagnosed with schizophrenia with low level PTSD symptoms. Results supported a vulnerability to neutral intrusive memories within the comorbid group, which did not seem to be related to psychotic symptom severity. It is possible that a subgroup of psychotic individuals’ process information in a manner that make them susceptible to frequent intrusive memories, characteristic of a PTSD presentation. A longitudinal study is required to specify the development of this vulnerability so as to inform future interventions.

Cognitive influences on the affective representation of touch and the sight of touch in the human brain

We show that the affective experience of touch and the sight of touch can be modulated by cognition, and investigate in an fMRI study where top-down cognitive modulations of bottom-up somatosensory and visual processing of touch and its affective value occur in the human brain. The cognitive modulation was produced by word labels, 'Rich moisturizing cream' or 'Basic cream', while cream was being applied to the forearm, or was seen being applied to a forearm. The subjective pleasantness and richness were modulated by the word labels, as were the fMRI activations to touch in parietal cortex area 7, the insula and ventral striatum. The cognitive labels influenced the activations to the sight of touch and also the correlations with pleasantness in the pregenual cingulate/orbitofrontal cortex and ventral striatum. Further evidence of how the orbitofrontal cortex is involved in affective aspects of touch was that touch to the forearm [which has C fiber Touch (CT) afferents sensitive to light touch] compared with touch to the glabrous skin of the hand (which does not) revealed activation in the mid-orbitofrontal cortex. This is of interest as previous studies have suggested that the CT system is important in affiliative caress-like touch between individuals.

Enhanced affective brain representations of chocolate in cravers vs. non-cravers

To examine the neural circuitry involved in food craving, in making food particularly appetitive and thus in driving wanting and eating, we used fMRI to measure the response to the flavour of chocolate, the sight of chocolate and their combination in cravers vs. non-cravers. Statistical parametric mapping (SPM) analyses showed that the sight of chocolate produced more activation in chocolate cravers than non-cravers in the medial orbitofrontal cortex and ventral striatum. For cravers vs. non-cravers, a combination of a picture of chocolate with chocolate in the mouth produced a greater effect than the sum of the components (i.e. supralinearity) in the medial orbitofrontal cortex and pregenual cingulate cortex. Furthermore, the pleasantness ratings of the chocolate and chocolate-related stimuli had higher positive correlations with the fMRI blood oxygenation level-dependent signals in the pregenual cingulate cortex and medial orbitofrontal cortex in the cravers than in the non-cravers. To our knowledge, this is the first study to show that there are differences between cravers and non-cravers in their responses to the sensory components of a craved food in the orbitofrontal cortex, ventral striatum and pregenual cingulate cortex, and that in some of these regions the differences are related to the subjective pleasantness of the craved foods. Understanding individual differences in brain responses to very pleasant foods helps in the understanding of the mechanisms that drive the liking for specific foods and thus intake of those foods.

Disorder-specific functional abnormalities during temporal discounting in youth with Attention Deficit Hyperactivity Disorder (ADHD), Autism and comorbid ADHD and Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share cognitive abnormalities in temporal foresight. A key question is whether shared cognitive phenotypes are based on common or different underlying pathophysiologies and whether comorbid patients have additive neurofunctional deficits, resemble one of the disorders or have a different pathophysiology. We compared age- and IQ-matched boys with non-comorbid ADHD (18), non-comorbid ASD (15), comorbid ADHD and ASD (13) and healthy controls (18) using functional magnetic resonance imaging (fMRI) during a temporal discounting task. Only the ASD and the comorbid groups discounted delayed rewards more steeply. The fMRI data showed both shared and disorder-specific abnormalities in the three groups relative to controls in their brain-behaviour associations. The comorbid group showed both unique and more severe brain-discounting associations than controls and the non-comorbid patient groups in temporal discounting areas of ventromedial and lateral prefrontal cortex, ventral striatum and anterior cingulate, suggesting that comorbidity is neither an endophenocopy of the two pure disorders nor an additive pathology.

Abnormal functional activation and maturation of fronto-striato-temporal and cerebellar regions during sustained attention in autism spectrum disorder

Objective Sustained attention problems are common in people with autism spectrum disorder (ASD) and may have significant implications for the diagnosis and management of ASD and associated comorbidities. Furthermore, ASD has been associated with atypical structural brain development. The authors used functional MRI to investigate the functional brain maturation of attention between childhood and adulthood in people with ASD. Method Using a parametrically modulated sustained attention/vigilance task, the authors examined brain activation and its linear correlation with age between childhood and adulthood in 46 healthy male adolescents and adults (ages 11–35 years) with ASD and 44 age- and IQ-matched typically developing comparison subjects. Results Relative to the comparison group, the ASD group had significantly poorer task performance and significantly lower activation in inferior prefrontal cortical, medial prefrontal cortical, striato-thalamic, and lateral cerebellar regions. A conjunction analysis of this analysis with group differences in brain-age correlations showed that the comparison group, but not the ASD group, had significantly progressively increased activation with age in these regions between childhood and adulthood, suggesting abnormal functional brain maturation in ASD. Several regions that showed both abnormal activation and functional maturation were associated with poorer task performance and clinical measures of ASD and inattention. Conclusions The results provide first evidence that abnormalities in sustained attention networks in individuals with ASD are associated with underlying abnormalities in the functional brain maturation of these networks between late childhood and adulthood.

Children and adolescents referred for treatment of anxiety disorders: differences in clinical characteristics

Background: Reports of the clinical characteristics of children and adolescents with anxiety disorders are typically based on community populations or from clinical samples with exclusion criterion applied. Little is known about the clinical characteristics of children and adolescents routinely referred for treatment for anxiety disorders. Furthermore, children and adolescents are typically treated as one homogeneous group although they may differ in ways that are clinically meaningful. Methods: A consecutive series of children (n = 100, aged 6-12 years) and adolescents (n = 100, aged 13-18 years), referred to a routine clinical service, were assessed for anxiety and comorbid disorders, school refusal and parental symptoms of psychopathology. Results: Children were significantly more likely to be diagnosed with separation anxiety disorder than adolescents. Adolescents with a primary anxiety disorder had significantly higher self and clinician rated anxiety symptoms and had more frequent primary diagnoses of social anxiety disorder, diagnoses and symptoms of mood disorders, and irregular school attendance. Limitations: Childhood and adolescence were considered categorically as distinct, developmental periods; in reality changes would be unlikely to occur in such a discrete manner. Conclusions: The finding that children and adolescents with anxiety disorders have distinct clinical characteristics has clear implications for treatment. Simply adapting treatments designed for children to make the materials more ‘adolescent-friendly’ is unlikely to sufficiently meet the needs of adolescents.

The experience of friendship, victimization and bullying in children with an autism spectrum disorder: associations with child characteristics and school placement

Children with an autism spectrum disorder (ASD) may be vulnerable to social isolation and bullying. We measured the friendship, fighting/bullying and victimization experiences of 10–12-year-old children with an ASD (N = 100) using parent, teacher and child self-report. Parent and teacher reports were compared to an IQ-matched group of children with special educational needs (SEN) without ASD (N = 80) and UK population data. Parents and teachers reported a lower prevalence of friendships compared to population norms and to children with SEN without an ASD. Parents but not teachers reported higher levels of victimization than the SEN group. Half of the children with an ASD reported having friendships that involved mutuality. By teacher report children with an ASD who were less socially impaired in mainstream school experienced higher levels of victimization than more socially impaired children; whereas for more socially impaired children victimization did not vary by school placement. Strategies are required to support and improve the social interaction skills of children with an ASD, to enable them to develop and maintain meaningful peer friendships and avoid victimization.

Observing interactions between children and adolescents and their parents: the effects of anxiety disorder and age

Parental behaviors, most notably overcontrol, lack of warmth and expressed anxiety, have been implicated in models of the development and maintenance of anxiety disorders in children and young people. Theories of normative development have proposed that different parental responses are required to support emotional development in childhood and adolescence, yet age has not typically been taken into account in studies of parenting and anxiety disorders. In order to identify whether associations between anxiety disorder status and parenting differ in children and adolescents, we compared observed behaviors of parents of children (7–10 years) and adolescents (13–16 years) with and without anxiety disorders (n=120), while they undertook a series of mildly anxiety-provoking tasks. Parents of adolescents showed significantly lower levels of expressed anxiety, intrusiveness and warm engagement than parents of children. Furthermore, offspring age moderated the association between anxiety disorder status and parenting behaviors. Specifically, parents of adolescents with anxiety disorders showed higher intrusiveness and lower warm engagement than parents of non-anxious adolescents. A similar relationship between these parenting behaviors and anxiety disorder status was not observed among parents of children. The findings suggest that theoretical accounts of the role of parental behaviors in anxiety disorders in children and adolescents should distinguish between these different developmental periods. Further experimental research to establish causality, however, would be required before committing additional resources to targeting parenting factors within treatment.

Interpretation and expectations among mothers of children with anxiety disorders: associations with maternal anxiety disorder

Background Models of the development and maintenance of childhood anxiety suggest an important role for parent cognitions: that is, negative expectations of children's coping abilities lead to parenting behaviors that maintain child anxiety. The primary aims of the current study were to (1) compare expectations of child vulnerability and coping among mothers of children with anxiety disorders on the basis of whether or not mothers also had a current anxiety disorder, and (2) examine the degree to which the association between maternal anxiety disorder status and child coping expectations was mediated by how mothers interpreted ambiguous material that referred to their own experience. Methods The association between interpretations of threat, negative emotion, and control was assessed using hypothetical ambiguous scenarios in a sample of 271 anxious and nonanxious mothers of 7- to 12-year-old children with an anxiety disorder. Mothers also rated their expectations when presented with real life challenge tasks. Results There was a significant association between maternal anxiety disorder status and negative expectations of child coping behaviors. Mothers’ self-referent interpretations were found to mediate this relationship. Responses to ambiguous hypothetical scenarios correlated significantly with responses to real life challenge tasks. Conclusions Treatments for childhood anxiety disorders in the context of parental anxiety disorders may benefit from the inclusion of a component to directly address parental cognitions. Some inconsistencies were found when comparing maternal expectations in response to hypothetical scenarios with real life challenges. This should be addressed in future research.

Trajectories of maternal depression and offspring psychopathology at 6 years: 2004 Pelotas cohort study

BACKGROUND: Few studies have addressed the course and severity of maternal depression and its effects on child psychiatric disorders from a longitudinal perspective. This study aimed to identify longitudinal patterns of maternal depression and to evaluate whether distinct depression trajectories predict particular psychiatric disorders in offspring. METHODS: Cohort of 4231 births followed-up in the city of Pelotas, Brazil. Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) at 3, 12, 24 and 48 months and 6 years after delivery. Psychiatric disorders in 6-year-old children were evaluated through the development and well-being assessment (DAWBA) instrument. Trajectories of maternal depression were calculated using a group-based modelling approach. RESULTS: We identified five trajectories of maternal depressive symptoms: a "low" trajectory (34.8%), a "moderate low" (40.9%), a "increasing" (9.0%), a "decreasing" (9.9%), and a "high-chronic" trajectory (5.4%). The probability of children having any psychiatric disorder, as well as both internalizing and externalizing problems, increased as we moved from the "low" to the "high-chronic" trajectory. These differences were not explained by maternal and child characteristics examined in multivariate analyses. LIMITATIONS: Data on maternal depression at 3-months was available on only a sub-sample. In addition, we had to rely on maternal report of child's behavior alone. CONCLUSIONS: The study revealed an additive effect on child outcome of maternal depression over time. We identified a group of mothers with chronic and severe symptoms of depression throughout the first six years of the child life and for this group child psychiatric outcome was particularly compromised.